Der Verfall des englischen Planungssystems - das Beispiel von Londons Docklands

Wissenschaftliches Kolloquium vom 27. bis 30. Juni 1989 in Weimar an der Hochschule für Architektur und Bauwesen zum Thema: ‚Produktivkraftentwicklung und Umweltgestaltung. Sozialer und wissenschaftlich-technischer Fortschritt in ihren Auswirkungen auf Architektur und industrielle Formgestaltung in unserer Zeit. Zum 100. Geburtstag von Hannes Meyer

The Effects of Accentuated Eccentric Loading on Barbell and Trap Bar Countermovement Jumps

This study examined effects of accentuated eccentric loading (AEL) on barbell and trap bar loaded countermovement jumps (LCMJ). Twenty-one subjects (16 male, 5 female; Age: 23.5 ± 1.8 years; Body mass: 81.4 ± 10.6 kg; Height: 176.9 ± 7.2 cm; Training age: 7.1 ± 2.6 years) participated in this study. Upon establishing one repetition maximum and baseline jumping conditions, three experimental loading sessions were completed in random order. Barbell and trap bar LCMJ were performed with a spectrum of fixed loads from 20-50 kg during control conditions and with additional AEL loads of 10, 20, or 30 kg for experimental conditions. According to coefficients of variation

Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk

Genetic contributions to variation in general cognitive function:a meta-analysis of genome-wide association studies in the CHARGE consortium (<i>N</i>=53 949)

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C

Role of catecholate siderophores in gram-negative bacterial colonization of the mouse gut

We investigated the importance of the production of catecholate siderophores, and the utilization of their iron (III) complexes, to colonization of the mouse intestinal tract by Escherichia coli. First, a ΔtonB strain was completely unable to colonize mice. Next, we compared wild type E. coli MG1655 to its derivatives carrying site-directed mutations of genes for enterobactin synthesis (ΔentA::Cm; strain CAT0), ferric catecholate transport (Δfiu, ΔfepA, Δcir, ΔfecA::Cm; CAT4), or both (Δfiu, ΔfepA, ΔfecA, Δcir, ΔentA::Cm; CAT40) during colonization of the mouse gut. Competitions between wild type and mutant strains over a 2-week period in vivo showed impairment of all the genetically engineered bacteria relative to MG1655. CAT0, CAT4 and CAT40 colonized mice 10[superscript 1]-, 10[superscript 5]-, and 10[superscript 2]-fold less efficiently, respectively, than MG1655. Unexpectedly, the additional inability of CAT40 to synthesize enterobactin resulted in a 1000-fold better colonization efficiency relative to CAT4. Analyses of gut mucus showed that CAT4 hyperexcreted enterobactin in vivo, effectively rendering the catecholate transport-deficient strain iron-starved. The results demonstrate that, contrary to prior reports, iron acquisition via catecholate siderophores plays a fundamental role in bacterial colonization of the murine intestinal tract

Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and isoform profile

The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, encoded on chromosome 5q15, trim endogenous peptides for human leukocyte antigen (HLA) mediated presentation to the immune system. Polymorphisms in ERAP1 and/or ERAP2 are strongly associated with several immune-mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as a prerequisite for autoreactivity against an arthritogenic peptide. Given the thorough characterisation of disease risk-associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression.RNA sequencing and genotyping across chromosome 5q15 was used to detect genetic variants in ERAP1 and ERAP2 associated with altered total gene and isoform-specific expression. The functional implication of a putative mRNA splice-altering variant on ERAP1 protein levels was validated using mass spectrometry.Polymorphisms associated with ankylosing spondylitis significantly influence the transcript and protein expression of the ERAP aminopeptidases. Disease risk-associated polymorphisms in and around both genes are also associated with increased gene expression. Furthermore, key risk-associated ERAP1 variants are associated with altered transcript splicing, leading to allele-dependent alternate expression of two distinct isoforms, and significant differences in the type of ERAP1 protein produced.In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the elevated risk also attributed to increased expression of ERAP1 and ERAP2 supports the therapeutic notion of aminopeptidase inhibition to treat AS and other ERAP associated conditions. This article is protected by copyright. All rights reserved